Calcineurin (CaN), also called protein phosphatase 2B (PP2B), belongs to serine/threonine protein phosphatase family. Up to date, CaN is the only one serine/threonine protein phosphatase which is regulated by Ca2+/calmodulin (CaM). CaN executes its functions through removing the phosphate from its substrates. In T cells, Ca2+ influx increases intracellular Ca2+ concentration, and then Ca2+ binds to CaM and CaN, activates CaN. After activated CaN removes the phosphate from its substrate NF-AT, the substrates enter cell nucleus and activate the expression of some cytokines including IL-2. CaN-FN-AT pathway plays a key regulative role in T cells activation.
At present, calcineurin inhibitor is the most effective immunosuppressive agent in clinic. It is used in organ transplantation, the control of transplantation rejection and the treatment of autoimmune diseases (RA, CD, psoriasis). In particular, it has a satisfied effect on the treatments of skin allergic and skin inflammation (such as eczema) in recent years. As an immunosuppressive agent, calcineurin inhibitors (CNIs) are divided into exogenous inhibitors and endogenous protein inhibitors. Exogenous inhibitors include cyclosporine, tacrolimus, etc. Endogenous protein inhibitors include Cain, FKBP38, etc. To date, the most popular CNIs in clinic are ascomycin derivatives including cyclosporine A, tacrolimus and pimecrolimus. These inhibitors have similar physical-chemical properties, mechanisms and effects, but their toxicity and side-effect (such as nephrotoxicity, hyperglycaemia, etc.) are big barriers for their application. Therefore, finding more effective and safer calcineurin inhibitors, which target CaN-NF-AT pathway, is important in the new type skin inflammation drug development.
Chinese medicine is the traditional medicine in China, and in clinic, Chinese medicine shows fairly good effect on the treatments of skin inflammation (such as eczema) and autoimmune diseases. Recent research found that some active ingredients in Chinese medicine (such as quercetin, kaempferol, phenolic gossypol) can bind to CaN directly and inhibit its activity. Also, some active ingredients of Chinese medicine (such as cordycepin, farrerol, fisetin) can inhibit the activation of CaN-NF-AT pathway at the cellular level, thus inhibit the expression of type Th1 and Th2 cytokines as well as the activation of T cells. Chinese medicine has the properties of wide material source, low cost and low toxicity, so it should be widely used. Through reasonable Chinese medical formulas, Chinese medicine will have at least the same effect as Western medicine on the treatment of skin inflammation, and can be used in the cosmetics which have anti-allergic and skin relax function.